JP5897026B2 - Medicinal module for inhaler - Google Patents

Description

  The application, in one embodiment, uses at least two drug agents with an inhaler device configured for single user inhalation through a single dose interface (ie, a mouthpiece). Relates to a medical device and method for delivering the drug from separate reservoirs or containers. The delivery procedure initiated by the user is such that a non-user settable dose (ie, a fixed dose) of the second drug agent combined with the set dose of the first drug agent is delivered to the patient. Let Drug agents are available in two or more reservoirs, containers, or packaging, each of which is an independent (single drug compound) or premixed (co-formulated multi-drug compound (co-formulated multiple drug compounds)) containing drug agents. Another embodiment relates to delivering one drug agent.

  Certain diseases require treatment with one or more different drugs. Some drug compounds need to be delivered in a specific relationship to each other in order to deliver the optimal therapeutic dose. The present invention is particularly advantageous when combination therapy is desirable but not limited and is not possible with a single formulation for reasons such as stability, poor therapeutic efficacy, and / or toxicity.

  For example, in some cases it may be advantageous to treat patients suffering from diabetes with a combination of long acting insulin combined with glucagon-like peptide-1 (GLP-1). This GLP-1 is derived from the transcription product of the proglucagon gene. GLP-1 is found in the body and is secreted by intestinal L cells as a gastrointestinal hormone. GLP-1 has several physiological properties that make it (and its analogs) subject to extensive investigation as a possible treatment for diabetes. Alternatively, other combinations of drugs that treat asthma, such as LABA (long acting beta agonist) and corticosteroids may be used in the present invention.

  Many potential problems can arise when delivering two drugs or “agents” simultaneously. By way of example only, two active agents when in a single container can interact with each other during long term, shelf life storage of the formulation. It is therefore advantageous to store the active ingredients separately and then simply combine them at the time of delivery, eg injection, needleless injection, pump, or inhalation. However, any possible way of combining two or more agents needs to be simple and convenient so that the user can perform iteratively and safely.

  One further concern is that the possible combination doses and the amount and / or proportion of each active agent that make up the therapy may need to be changed at each user or at different stages of their therapy. However, by way of example only, one or more active agents may require a titration period to gradually lead the patient to a “maintenance” dose. A further example is where one active agent requires an unadjusted fixed dose while the other agent varies depending on the patient's symptoms or physical condition. This potential concern is that premix formulations of multiple active agents are not suitable because these premix formulations may have a fixed ratio of active ingredients that cannot be varied by medical personnel or users. It can mean that there is a possibility.

  A further concern is that a multi-drug compound can be addressed because some users must use more than one drug delivery system or need to make the necessary accurate calculations of the required dose combination. It can occur when therapy is needed. This is especially true for users who are dexterous or difficult to calculate.

  Thus, a single inhaler-type drug delivery device, such as a dry powder inhaler, that is easy and safe for the user to perform and also tends to reduce patient anxiety by taking repeated doses of the drug In activation, there is a strong need to provide devices and methods for the delivery of two or more drugs.

  This application provides one or more predetermined doses of secondary inhalation medication automatically into a patient's exhaled air flow through an inhaler device containing one or more doses of a primary or first agent. Disclosed is a medicated module that can be attached to an inhaler device, preferably a dry powder inhaler (DPI), to provide a means for delivering a dose. Single-use medicinal modules containing secondary drugs (such as corticosteroids), and standard multiple times such as "Disk-halers" containing primary drugs (such as bronchodilators) Such a dry powder inhalation system that combines the DPI device used thereby provides a means for the user / patient to receive a combined dose of at least two drugs during a single inhalation, thus the complexity of storage and operation Reduce the burden on

  Alternatively, the medicated module can be used in an inhaler that does not contain a first drug, eg, an inhaler from which all drugs are being dispensed. In this case, the secondary drug of the module may be the only drug in the inhaler drug delivery system comprising the inhaler device and the medicated module.

  Accordingly, the inhaler drug delivery system of the present invention includes the medicated module and dry powder inhaler housing of the present invention in combination. In one embodiment, the dry powder inhaler housing may further include a powder drug reservoir.

  The medicinal module ensures that the flow shape design of the medicinal module does not compromise the air flow induced de-aggregation forces generated in the primary DPI device, thereby delivering the delivery dose performance (eg, , Fine particle fraction, FPF or fine particle mass, FPM). Careful selection of the geometry within the medicated module housing can minimize the possibility of significant changes to the airflow resistance (AFR) of the system, while also reducing the powder in the airflow path to a practical extent. Reduce the chance of deposition. The intent is to ensure excellent comparability between primary drug delivery dose performance from the primary device when doing so, as well as when used in combination with a medicated module It is to contribute to.

  The medicated module of the present invention comprises means containing a second drug in a drug cavity located in the housing of the medicated module. Preferably, the second drug is most preferably a single dose contained in a primary pack or container such as a single cavity blister of the type known in the art. Such blisters can be made from cold-formed sheet or strip material and can be made from a single material type or from multi-layer materials (plastic (eg PVC) and aluminum laminate). When the blister pocket containing the second agent can be sealed by the upper foil (or similar) and is actuated by an upright (or similar) function that may be present in the blister cavity, such as a compression force, preferably It may be releasably attached by a base foil or configured to facilitate controllable rupture. Both means of accessing the dry powder formulation contained in the blister are known in the art. Alternative forms of blisters such as injection molded cavities in plastics (eg POM, COC, PBT, COP or combinations) are also possible.

  One advantage of the proposed system is that the secondary drug is automatically introduced into the air flow path when the medicated module is attached to the standard inhaler. Preferably, the connection between the mouthpiece of the primary inhaler device and the inlet port of the medicated module can be configured to help ensure that minimal bypass airflow occurs at this joint during inhalation, and therefore Helps maintain delivery dosage performance and minimizes possible AFR variability.

The system can also be configured to help ensure that only the medicated module can be used only once by the user. This can be achieved through the integration of a mechanical valve (or similar air flow restriction means) that is activated (closed) only after inhalation by the user through the device. The purpose of any such mechanism or function can be to prevent / significantly restrict subsequent further air flow through the medicated module, thereby warning the user of this situation. Alternatively and / or in addition, the present invention may include the following functions;
1. Prevent reattachment of the used medicated module to the primary drug delivery device.
2. Visual alert once the blister has been opened (eg warning text / indicia in the display window on the module).

  Prior to use, i.e., attachment to the inhaler, the medicated module comprises a means for containing the second drug in a sealed drug cavity or reservoir. Possible materials that can be used to form a drug cavity that holds the second drug are: acetal (polyoxymethylene, polyacetal or polyformaldehyde), COC (cycloolefin copolymer), COP (cycloolefin polymer) And PBT (polybutylene terephthalate) may be included (but is not limited to). Sealing the reservoir in the medicated module can be accomplished through a foil seal (single or multi-layer), stopcock, septum combination or similar means known in the art.

  Upon assembly into the primary device, the container in the medicated module is automatically engaged (ie, opened), thus exposing the drug to the airflow scouring, or allowing the second drug to move distal to the medicated module. At the end, it is deposited in an exit orifice, ie a deagglomeration chamber in the flow path to the mouthpiece. Preferably, the coupling in the flow path can be established using a compliant material such as rubber or TPE, and to help ensure that minimal leakage or no leakage occurs during dosing. Thus, delivery dose efficiency is maintained. Engaging the fluid flow path of the medicated module with the fluid flow path of the first drug in the inhaler automatically simplifies user interaction with the device during assembly.

  In one embodiment of the invention, a medicated module for use with a drug inhaler includes a housing configured for removable attachment to the mouthpiece of the inhaler, wherein the housing is at the distal end and near. It has a position end. There is at least one drug container contained within a housing containing at least one dose of the second drug. When the medicated module is attached to the inhaler, the medicated module can also have a sliding member that opens the container. Alternatively, when the container moves relative to the outer housing portion of the medicated module, the sliding member opens the container by compression. Most preferably, the container is a blister.

  In yet another embodiment, the present invention includes a system of one or more previously described medicated modules in combination with a dry powder inhaler containing a primary drug.

  In one embodiment of the invention, the medicated module may include a flow path extending between the first opening and the second opening. In one embodiment, the deagglomeration chamber can be in fluid communication with the flow path. In another embodiment, the first opening may be configured as an exit orifice, eg, a modular mouthpiece. In another embodiment, the second opening can be configured to provide fluid communication between the flow path and the inhaler.

  In a preferred embodiment, a multi-dose, basic drug compound such as insulin contained in a user-selectable device is a single-use, user-replaceable module and single-use containing a single dose of a secondary drug. It can be used in a medication interface. When coupled to a drug delivery device, the secondary compound is activated / delivered upon administration of the primary compound. While this application specifically describes insulin, two possible drug combinations include insulin analogs or insulin derivatives, and other GLP-1 or GLP-1 analogs, analgesics, hormones, beta agonists or corticosteroids, etc. Or a combination of any of the above drugs may be used in the present invention.

  For the purposes of our invention, the term “insulin” shall mean insulin, insulin analogs, insulin derivatives or mixtures thereof, including human insulin or human insulin analogs or derivatives. Examples of insulin analogues are not limited and include Gly (A21), Arg (B31), Arg (B32) human insulin; Lys (B3), Glu (B29) human insulin; Lys (B28), Pro (B29) ) Human insulin; Asp (B28) human insulin; human insulin, where the proline at position B28 may be replaced by Asp, Lys, Leu, Val or Ala, and where at position B29, Lys may be replaced by Pro Ala (B26) human insulin; Des (B28-B30) human insulin; Des (B27) human insulin or Des (B30) human insulin. Examples of insulin derivatives include, but are not limited to, B29-N-myristoyl-des (B30) human insulin; B29-N-palmitoyl-des (B30) human insulin; B29-N-myristoyl-human insulin; B29- N-palmitoyl human insulin; B28-N-myristoyl-LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30N human insulin; (N-palmitoyl-γ-glutamyl) -des (B30) human insulin; B29-N- (N-ritocryl-γ-glutamyl) -des (B30) human insulin B29-N- (ω-carboxyheptadecanoyl) -des (B30) human insulin and B29-N- (ω-carboxyheptadecanoyl) human insulin.

The term “GLP-1” as used herein is not limited and is exenatide (exendin-4 (1-39), sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr- Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2) peptide, exendin-3, liraglutide, or AVE0010 (H-His-Gly- Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu -Ser-Lys-Gln-Met-Glu-Glu-Glu-Alu-Val-Arg- eu-Phe-Ile-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH 2 ), GLP-1, GLP-1 analog, or a mixture thereof.

  Examples of beta agonists are not limited, but are salbutamol, levosalbutamol, terbutaline, pyrbuterol, procaterol, metaproterenol, fenoterol, vitorterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol.

  Hormones include gonadotropins (folytropin, lutropin, corion gonadotropin, menotropin), somatropin (somatropin), desmopressin, telluripressin, gonadorelin, triptorelin, leuprorelin, buserelin, nafarelin, goserelin, etc. Hormones or regulatory active peptides and their antagonists.

  As used herein, the term “drug” or “medicament” means at least one for the treatment of obstructive airways or lung diseases such as asthma or chronic obstructive pulmonary disease (COPD), allergies, diabetes, for example. It means a pharmaceutical preparation containing one pharmaceutically active compound.

  The active pharmaceutical compound is preferably selected from the group consisting of active pharmaceutical compounds suitable for inhalation, preferably antiallergic agents, antihistamines, anti-inflammatory agents, antitussives, bronchodilators, anticholinergics, and combinations thereof. The

The active pharmaceutical compound can be selected, for example, from:
Insulin such as human insulin, for example recombinant human insulin, or human insulin analog or derivative, glycagon-like peptide (GLP-1) or analog or derivative thereof, or exendin-3 or exendin-4 or exendin-3 or exendin -4 analogs or derivatives;
Short-acting β2 agonists (eg salbutamol, albuterol, levosalbutamol, fenoterol, terbutaline, pyrbuterol, procaterol, vitorterol, limiterol, carbuterol, tulobuterol, reproterol), long-acting β2 agonists (LABA, eg, formoterol, bambuterol, Adrenergic drugs such as clenbuterol, formoterol, salmeterol), ultra-LABA (eg indacaterol), or other adrenergic drugs (eg epinephrine, hexoprenalin, isoprenaline (isoproterenol), orciprenaline, (metaproterenol));
Glucocorticoids (eg beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, flunisolide, betamethasone, triamcinolone);
An anticholinergic or muscarinic antagonist (eg ipratropium bromide, oxitropium bromide, tiotropium bromide);
A mast cell stabilizer (eg cromoglycic acid, nedocromil);
Xanthine derivatives (eg doxophilin, enprofylline, theobromine, theophylline, aminophylline, choline theophylline);
An eicosanoid inhibitor such as a leukotriene antagonist (eg montelukast, pranlukast, zafirlukast), a lipoxygenase inhibitor (eg zileuton), or a thromboxane receptor antagonist (eg ramatroban, seratrodast);
Or any two, three or more of the above compound types or combinations of compounds (budesonide / formoterol, fluticasone / salmeterol, ipratropium bromide / salbutamol, mometasone / formoterol);
Or a pharmaceutically acceptable salt or solvate or ester of any of the above specified compounds.

Pharmaceutically acceptable salts are, for example, acid addition salts and basic salts. Acid addition salts include, for example, chloride, bromide, iodide, nitrate, carbonate, sulfate, methyl sulfate, phosphate, acetate, benzoate, benzenesulfonate, fumarate, malonate, Tartrate, succinate, citrate, lactate, gluconate, glutamate, edetate, mesylate, pamoate, pantothenate or hydroxynaphthoate. Basic salts are, for example, cations selected from alkali or alkaline earth metals, such as Na ⁺ , K ⁺ , or Ca ²⁺ , or ammonium ions N ⁺ (R1) (R2) (R3) Wherein R1 to R4 are independently of each other hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted C6. A C10 aryl group, or an optionally substituted C6-C10 heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (edited), Mark Publishing, Easton, Pa., USA, 1985 and Encyclopedia of Pharmaceutical Technology. Yes. The pharmaceutically acceptable ester can be, for example, acetate, propionate, phosphate, succinate or etabonates.

  A pharmaceutically acceptable solvate is, for example, a hydrate.

  These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings.

  Exemplary embodiments are described herein below with reference to the drawings:

Figure 2 illustrates a perspective view of one possible drug delivery system of the present invention, wherein the medicated module of the present invention is shown attached to the mouthpiece of the inhaler. Fig. 4 illustrates a cross-sectional view of one arrangement of medicated modules before being attached to an inhaler. FIG. 3 illustrates a cross-sectional view of the medicated module illustrated in FIG. 2 after full attachment to the mouthpiece of the inhaler. Fig. 4 illustrates another type of cross-sectional view of the medicated module of the present invention prior to attachment to the mouthpiece of the inhaler. FIG. 5 illustrates a cross-sectional view of the medicated module of FIG. 4 after attachment to the inhaler.

  The proposed medicinal module may be used in an inhaler type drug delivery device such as the inhaler 2 illustrated in FIG. In one arrangement, the proposed medicinal module combines one or more single doses of a second drug with a fixed dose of the first drug from a multiple dose reservoir or blister pack in the inhaler. At the same time, it is administered through a single drain or drug dosing interface such as the module mouthpiece 11. For example, a single activation of the inhaler 2 by user inhalation may cause both the first and second medications to be delivered to the user. The volume and size of the second drug dose is independently controlled by the design and fabrication of reservoirs, containers, drug cavities, blisters, etc. in the medicated module, and hence the size of the dose generated by the inhaler at start-up. Not affected. This fixed dose of the second drug contained within the medicated module may be a single dose.

  In a preferred arrangement, the drug dispensing interface includes a modular mouthpiece, such as the mouthpiece 11 shown in FIGS. 1-5, however any channel or flow path that is capable of passing a flow of dry powder may be used. . As shown in FIG. 1, the module 1 includes a housing 5 that is preferably designed and configured to be removably attached in a direction 6 to a standard inhaler 2. A preferred arrangement is that the housing 5 of the medicated module 1 can be inserted beyond the mouthpiece 3 of the inhaler 2. The housing 5 may be any reversible connection means known in the art, such as threads, snap locks, snap fits, detents, luer locks, bayonets, snap rings, keyed slots, and combinations of such fittings. Is held in place. Preferably, the attachment mechanism between the medicated module and the inhaler allows the user to easily attach the module to the inhaler and then easily remove the module after discharging the second drug contained in the module. Configured to be able to. In some applications, a connector or mounting configuration is such dedicated mounting such that such a medicated module is attached to only one type of inhaler drug delivery device and to other types of inhalers or other drug delivery devices. Dedicated attachments may be included where it may only be possible to be prevented from being attached. Once the module is removed, the inhaler can then be used as a stand-alone drug delivery device to administer the first or primary drug.

  The inhaler device 2 shown in FIG. 1 is a dry powder inhaler (DPI) that typically contains multiple doses of a first drug during a blister pack deployment. Although a specific design of a DPI is illustrated, other types of DPI may also be suitable for use with the present invention. Alternatively, the medicated module can be used in an inhaler that does not contain a first drug, eg, an inhaler from which all drugs are being dispensed. In this case, the second drug of the module according to the specification may be the only drug in the inhaler drug delivery system. Reference is now made to FIGS. 3 and 4, which show enlarged views of a cross-sectional view of one embodiment of the medicated module 1. FIG. 2 shows the module before it is fully attached to the inhaler 2 when the container 20, shown as a blister, contains the second drug and is sealed by the seal 7. A seal 7 is also attached to the housing 5. The housing 5 is connected to a container 20 and has a sliding member 8 that moves in direction 9 when the module 1 is fully attached to the mouthpiece 3 of the inhaler 2.

  FIG. 3 shows the module 1 attached to the inhaler 2. The sliding member 8 and the container 20 are moved distally so that the container 20 is positioned beyond the deagglomeration chamber 4. As the sliding member 8 and the container 20 move, the seal 7 is peeled or pulled away from the underside of the container just before being positioned beyond the deagglomeration chamber 4. The drug is preferably kept in the container 20 due to the cohesive force generated by the compaction of the drug during filling of the container. The user operates the combination of the medicated module 1 and the inhaler 2 exactly in the same manner as when the module is not attached. Upon successful completion of any primary device setup operation (priming level activation, etc.), when the user inhales with the mouthpiece 11 of the medicated module 1, the air flow due to the transported powdered first agent is inhaled Through the vessel mouthpiece 3, through the housing 5, and then through the disaggregation chamber 4, where the second drug is also transported as stream 31, and the flow mix of the two drugs, 30 and 31, then passes through the medicated module mouthpiece 11. Inhaled and administered to the user. As soon as air begins to flow from the primary device and reaches the container, the secondary drug can initiate transport.

  In one preferred arrangement, the container or blister 20 contains a single dose of a second agent, such as a single dose of an active agent such as GLP-1. Alternatively, the reservoir contains a single dose of pre-mix of active agent or drug. In one preferred arrangement, the primary agent comprises a different type of agent than the agent contained within the drug delivery device.

  4 and 5 illustrate another possible embodiment of the medicated module of the present invention when it is a compressible container, such as a blister, that is configured to open the container 20 when compressed. FIG. 4 illustrates the medicated module 1 prior to attachment to the inhaler 2. The container 20 is sealed along at least one surface with a seal 7. When the medicated module is attached to the inhaler 2, the sliding member 8 of the housing 5 moves in the direction 9. This sliding member 8 thereby carries the container 20, the deagglomeration chamber 4 and the internal flow path 32. As the container 20 moves distally, it becomes compressed due to the narrowing of the outer portion 33 of the housing 5. Since the relative positioning of the container 20 and the deagglomeration chamber 4 is fixed, compression and opening of the container 20 can cause the second drug to fall into the chamber 4.

  Similar to the above embodiment, the user operates the combination of the medicated module 1 and the inhaler 2 exactly as they are when the module is not attached. Upon successful completion of any primary device setup operation (priming level activation, etc.), when the user inhales with the mouthpiece 11 of the medicated module 1, the air flow due to the transported powdered first agent is inhaled Through the mouthpiece 2, through the housing 5, and then through the deagglomeration chamber 4, where the second drug is also transported as stream 31, and the flow of the two drugs, 30 and 31, is then inhaled through the medicated module mouthpiece 11 And administered to the user.

  It is within the scope of the present invention to configure a medicated module with a locking mechanism to lock and / or block the distal end, proximal end, or both after dose administration. One advantage of locking the medicinal module from repeated use is that the user can be prevented from reusing the used medicinal module, and as a result, the primary user saved male and female users in the new medicinal module. It is possible to rule out the possibility that the user can use the used medicated module given that he has received a pre-defined dose of the drug. Similarly, such a blocking / locking feature prevents a user from reusing a non-sterile pharmaceutical module after a dose has been delivered.

  The medicated module arrangement disclosed herein is preferably self-contained and can be provided as a sealed and sterile disposable module. Although not shown, the medicated module disclosed herein is in a protective and sterile capsule or container if the user can peel or open the seal or container itself to gain access to the sterile medicated module. Can be included and supplied by the manufacturer. In some cases, it may be desirable to provide two or more seals for each end of the medicated module. Moreover, in the arrangements described above, these arrangements are such that the second drug is contained entirely within the medicated module and separate from and separate from the first drug contained within the inhaler-type drug delivery device. There are advantages in being. Exemplary embodiments of the invention have been described. However, it will be apparent to one skilled in the art that changes or modifications may be made in these embodiments without departing from the true scope and spirit of the invention as defined by the claims.

Claims (11)

A medicated module configured for use with a drug inhaler, wherein the medicated module is:
An inhaler (2) having a distal end with a first opening and a proximal end with a second opening and a flow path extending between the first opening and the second opening; Housing (5) configured for attachment to
A drug container (20) containing a dose of the drug;
A deagglomeration chamber (4) configured to receive the drug from the container upon opening of the container;
Wherein the medicated module is configured such that attachment to the drug inhaler automatically opens the container into the flow path , and
The medicated module further comprising a sliding member (8) that cooperates with the container (20) to open the container during attachment of the medicated module to the inhaler (2) . The medicinal module according to claim 1 , wherein the container (20) is movable and the container and the sliding member (8) move during attachment of the medicated module to the inhaler (2). The medicinal module according to claim 1 or 2 , wherein the container (20) and the deagglomeration chamber (4) are in fluid communication when the medicated module (1) is in the mounted state. The medicinal module according to claim 1 , wherein the container (20) is opened by a sliding member (8) that compresses the container against the outer part (33) of the housing (5). The medicinal module according to any one of claims 1 to 4 , wherein the container (20) is a blister. When the medicated module is attached, disaggregation chamber (4) is in fluid communication with the mouthpiece (3) of the inhaler (2), medicated module according to any one of claims 1-5. Disaggregation chamber (4) is in fluid flow path in fluid communication with, medicated module according to any one of claims 1-6. The medicinal module according to any one of claims 1 to 7 , wherein the first opening is configured as an outlet orifice, for example a mouthpiece of the module. The second opening is configured to provide fluid communication between the passage and the inhaler (2), medicated module according to any one of claims 1-8. 10. An inhaler drug delivery system comprising, in combination, a medicated module according to any one of claims 1 to 9 ; and a dry powder inhaler housing (2). The inhaler drug delivery system according to claim 10 , wherein the dry powder inhaler housing (2) further comprises a reservoir of powder medicament.

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